1. Field of the Invention
This invention relates to a method of enhancing oxygen availability to mammalian, especially human, tissue. More particulatly, the invention relates to modifying the affinity of hemoglobin for oxygen and thereby effecting adequate supply of oxygen to human tissue necessary for metabolism.
Certain clinical conditions are associated with increased demand for oxygen, namely, respiratory distress syndrome, shock, low cardiac output, heart and lung diseases, anemia, hyperthyroidism, cirrhosis of the liver, exercise, high altitude climbing and the like. Under these conditions it is desirable, and sometimes of life-saving necessity, to effect higher oxygen availability to the patient than is normally available. The present invention addresses methods and compositions to that end.
Blood circulating through the heart, arteries, veins and capillaries is vital to the functioning of the body, inter alia, for carrying nutriment and oxygen to the body cells and carbon dioxide back through the systemic veins for gas-exchange in the lungs. Blood consists of plasma containing the red blood corpuscles or erthrocytes, the white blood corpuscles or leukocytes, and blood platelets or thrombocytes. The oxygen transport system in man is the erythrocyte which contains the iron-protein conjugate, called hemoglobin. While the supply of oxygen to the cell is influenced by many factors, such as, the content and partial pressure of oxygen in the inhaled air, cardiac output and blood volume, the passive diffusion of oxygen from the lungs and its release to the tissues is mainly controlled by the affinity of hemoglobin for oxygen.
This affinity is expressed by an oxygen hemoglobin dissociation curve having oxygen tension denoted by mm Hg, and oxygen saturation denoted by percentage as the coordinates. At 50% oxygen saturation (P.sub.50) the oxygen tension is 27 mm Hg. An increase in blood acidity, carbon dioxide content, ionic concentration or temperature is known to shift the oxygen-hemoglobin equilibrium curve to the right by reducing hemoglobin affinity for oxygen and thereby increasing oxygen availability to the tissues. On the other hand, an increase in alkalinity of blood and tissues as well as a decrease in body temperature is known to shift the equilibrium curve to the left, and therefore, decrease oxygen availability.
Affinity of hemoglobin for oxygen is regulated by the level of certain intracellular organic phosphates, notably, 2,3-diphosphoglyceric acid (hereinafter 2,3-DPG). Thus, the equilibrium curve can be shifted from normal either to the left or to the right by changing the concentration of intracellular 2,3-DPG in the red blood cells. The synthesis of 2,3-DPG is catalyzed by the enzyme 2,3-diphosphoglycerate synthase, the stimulation of which results in the maintenance or accumulation of 2,3-DPG in red blood cells. The degradation of 2,3-DPG, on the other hand, is catalyzed by the enzyme 2,3-diphosphoglycerate phosphatase. The inhibition of this enzyme, similarly, would result in the maintenance and accumulation of 2,3-DPG in red blood cells, accompanied by the maintenance and increase of oxygen availability.
2. Description of the Prior Art
It has been recognized by the prior art that oxygen-hemoglobin affinity is mainly regulated by the level of 2,3-DPG in mammalian red blood cells. (See for example: Benesh et al., Intracellular organic phosphates as regulators of oxygen release by hemoglobin, Nature, London, 221: 618-622, 1969; Oski et al. The Interrelationship Between Red Blood Cell Metabolites, Hemaglobin, and the Oxygen-Equilibrium Curve, Progress in Hemotology 7: 33, 1971.) Clinical conditions associated with alterations of 2,3-DPG levels include adaptation to high altitude, anemia, cirrhosis of the liver, heart and lung diseases and hyperthyroidism. These relationships were investigated by, for example:
Keys et al., Respiratory properties of the arterial blood in normal man and with patients with disease of the liver. Position of the oxygen dissociation curve, J. Clin. Invest., 17:59, 1938;
Morse et al., The position of the oxygen dissociation curve of the blood in cyanotic congenital heart disease, J. Clin. Invest., 29:1098, 1950;
Edwards et al., Improved oxygen release: An adaptation of mature red cells to hypoxia, J. Clin. Invest. 47:1851-1857, 1968;
Gahlenbeck et al., Veraenderung der Saurstoffbindungskurven des Blutes by Hyperthyreosen und nach Gabe von Trijodthyronin bei Gesunden und bei Ratten. Klin. Wschr. 46:547, 1968:
Keys et al., The position of the oyxgen dissociation curve of human blood at high altitude, Amer. J. Physiol 115:292, 1936. Under these conditions delivery of oxygen to the tissues is imparied and the body's natural responses are inadequate to correct the tissue hypoxia.
To relieve hypoxic conditions, pharmaceutically active compounds, which shift the oxygen-hemoglobin dissociation curve to the right, were proposed and shown to be effective using appropriate test procedures. (See U.S. Pat. Nos. 4,626,431, 4,626,432 and EPO No. 0 093 381.) In addition to in vivo application, the compounds were also proposed for use in vitro blood storage to prolong useful shelf-life thereof. As to the mechanism or pathway involved in accomplishing the desired result, the compounds are said to induce right-displacement of the oxygen-dissociation curve.
The prior art has also discovered that the synthesis and degradation of 2,3-DPG are catalyzed by two enzymatic activities known respectively as 2,3-diphosphoglycerate synthase and 2,3-diphosphoglycerate phosphatase. (See: Rose, Z. B., J. Biol. Chem. 243, 4810, 1968 and Rose et al., J. Biol. Chem. 245, 3232, 1970.) Accordingly, the stimulation of 2,3-diphosophoglycerate phosphatase, or both, shall result in the maintenance or increase of 2,3-DPG levels in the red blood cells.
The present invention is drawn to the inhibition of 2,3-diphosphoglycerate phosphatase by the utilization of certain compounds found to be effective to accomplish said inhibition and thereby providing for the maintenance and/or accumulation of 2,3-DPG levels which, as shown by the prior art, control the dissociation of oxygen/ hemoglobin. The mechanism involved in the inhibition of 2,3-diphosphoglycerate phosphatase is believed to be as follows.
2,3-diphosphoglycerate phosphatase is activated by a number of cellular metabolites, such as 2-phosphoglycolate, chloride and phosphate ions. 2-Phosphoglycolate is by far the most potent activator enhancing the activity of 2,3-diphosphoglycerate phosphatase by about 1600 fold at optimal concentrations. Preventing or lowering the interaction of 2-phosphoglycolate with 2,3-diphosphoglycerate phosphatase affords an excellent mechanism to control the 2,3-DPG levels in the cells allowing utilization of inhibitors in low concentrations.
SUMMARY OF THE INVENTION
The present invention relates to naphthoic acid derivatives of formula I: ##STR1## wherein
R is H, alkyl, aryl or aminoalkyl;
R.sub.1 is H, alkyl, amino, NR.sub.3 R.sub.4 where R.sub.3 and R.sub.4 is H or alkyl, or R.sub.3 and R.sub.4 can form a cyclic amino group with N to which they are attached;
R.sub.2 is H, acyl, aminoacyl, alkyl, substituted alkyl wherein the substituents are aryl, cycloalkyl, azacycloalkyl, CONHR aryloxy, or alkoxyalkyl;
A is H, halo, CH.sub.3, OH or ##STR2## aminoalkyl, aryl, acyl, alkoxy, or alkoxyalkyloxy; and n is 0-6; and pharmaceutically acceptable salts thereof. These compounds have been heretofore known for their hypotensive activity. (U.S. Pat. No. 3,673,238 relates to such compounds and the same is incorporated herein by reference.)
In the above-denoted formula the various groups have the meanings that follow.
The alkyl group means alkyl having up to 8 carbon atoms and include straight-chained and branched groups, including methyl, ethyl, propyl, isopropyl, butyl, isobuty, tert-butyl, amyl, iso-amyl, heptyl, hexyl and the like. By halo is meant chloro, bromo, iodo, and fluoro.
Amino means amino or an amino derivative such as --NH.sub.2, --NH--C(NH.sub.2).dbd.NH when in formula I n is 2-6 or ##STR3##
The cyclic amino ring formed by R.sub.3 and R.sub.4 and the N atom to which they are attached contains 3 to 8 atoms.
The cycloalkyl group contains 3 to 10 carbon atoms; and the aryl group contains up to 12 carbon atoms. The preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, adamantyl or norbornyl. The preferred groups in aryl are phenyl and naphthyl.
Particularly preferred compounds are:
(a) 5-methoxy-3-hydroxy-2-naphthoic acid ##STR4##
(b) 5-phenetoxy-3-hydroxy-2-naphthoic acid ##STR5##
(c) 5-(3-trifluoromethylbenzyloxy)-3-hydroxy-2-naphthoic acid ##STR6##
(d) 5-phenoxyethoxy-3-hydroxy-2-naphthoic acid ##STR7##
(e) ethyl 5-(3-phenylpropoxy)-3-(2-diisopropylamino-ethoxy)-2-naphthoate ##STR8##
(f) ethyl 5-(3,4-dichlorobenzyloxy)-3-hydroxy-2-naphthoate ##STR9##
(g) 5-acetoxy-3-hydroxy-2-naphthoic acid ##STR10##
(h) 5-benzyloxy-3-hydroxy-2-naphthoic acid ##STR11##
(i) ethyl 5-(3-phenylpropoxy)-3-(2-piperidinoethoxy)-2-naphthoate ##STR12##
(j) ethyl 5-cyclohexylmethoxy-3-(2-(1-azacycloheptyl)-ethoxy)-2-naphthoate ##STR13##
(k) ethyl 5-cyclohexylmethoxy-3-diisopropylaminoethoxy-2-naphthoate ##STR14##
(l) ethyl 5-(4-chlorobenzyloxy)-3-diisopropylethoxy-2-naphthoate ##STR15##
(m) ethyl 5-benzyloxy-3-(3-dimethylamino)-propoxy-2-naphtoate ##STR16##
(o) 5-(4-fluorobenzyloxy)-3-acetoxy-2-naphthoic acid ##STR17##
(p) ethyl 3,5-bis[2-(1-pyrrolidinyl)ethoxy]-2-naphthoate monohydrochloride ##STR18##
(q) 5-(3,4-dichlorobenzyloxy)-3-hydroxy-2-naphthoic acid ##STR19##
(r) 3-hydroxy-5-(3-phenylpropoxy)-2-naphthoic acid ##STR20##
(s) 5-(2,4-dichlorobenzyloxy)-3-hydroxy-2-naphthoic acid ##STR21##
(t) 5-(2,6-dichlorobenzyloxy)-3-hydroxy-2-naphthoic acid ##STR22##
(u) 5-[3-(3,4-dichlorophenyl)-propoxy]-3-hydroxy-2-naphthoic acid ##STR23##
(v) 5-(4-fluorobenzyloxy)-3-hydroxy-2-naphthoic acid ##STR24##
(w) 3,5-bis-(3,4-dichlorobenzyloxy)-2-naphthoic acid ##STR25##
(x) 3-hydroxy-5(undecenyloxy)-2-naphthoic acid ##STR26##
(y) 5-benzyloxy-3-dichloroacetoxy-2-naphthoic acid ##STR27##
The pharmaceutically acceptable, non-toxic salts include salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric, and of organic acids such as acetic, propionic, glycolic, lectic, malonic, succinic, malic, fumaric, tartaric, citric, ascorbic, benzoic, hydroxybenzoic, aminosalicyclic, cinnamic, mandelic, benzenesulfonic, toluenesulfonic, nicotinic, isonicotinic, and the like.